Combined paediatric vaccines for national immunization programmes Francis E. André Vice-President...
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Transcript of Combined paediatric vaccines for national immunization programmes Francis E. André Vice-President...
Combined paediatric vaccines for national
immunization programmes
Francis E. André
Vice-President and senior Medical Director
GlaxoSmithKline, Rixensart, Belgium
Current shifts in pediatric immunization
Replacement of DTPw by DTPa
Introduction of universal hepatitis B vaccination
Introduction of universal Hib vaccination
Switch from OPV to IPV
SB DTPa-based pediatric combinationsSB DTPa-based pediatric combinations
DTP : Diphtheria/ Tetanus/ PT, FHA, PertactinHBV : Recombinant HBsAgIPV : Inactivated enhanced-potency polio vaccineHib : Lyophilized PRP-T conjugate
DTPa - HBV
DTPa
DTPa - IPV
DTPa - HBV - IPV
DTPa / Hib
DTPa - HBV / Hib
DTPa - IPV / Hib
DTPa - HBV - IPV / Hib
SB DTPa-based pediatric combinationsSB DTPa-based pediatric combinations
DTP : Diphtheria/ Tetanus/ PT, FHA, PertactinHBV : Recombinant HBsAgIPV : Inactivated enhanced-potency polio vaccineHib : Lyophilized PRP-T conjugate
DTPa - HBV
DTPa
DTPa - IPV
DTPa - HBV - IPV Infanrix penta
DTPa / Hib
DTPa - HBV / Hib
DTPa - IPV / Hib
DTPa - HBV - IPV / Hib Infanrix hexa
Infanrix penta
DTPa components
D: 25 Lf PT: 25 mcg
T: 10 Lf FHA: 25 mcg PRN: 8 mcg
Hepatitis B component
HBsAg: 10 mcg
Polio components
Polio 1: 40 DUPolio 2: 8 DUPolio 3: 32 DU
Excipients: Alum salts as adjuvant2-Phenoxyethanol as antiseptic
Infanrix penta and Infanrix hexa
DTPa components
D: 25 Lf PT: 25 mcg
T: 10 Lf FHA: 25 mcg PRN: 8 mcg
Hepatitis B component
HBsAg: 10 mcg
Polio components
Polio 1: 40 DUPolio 2: 8 DUPolio 3: 32 DU
Excipients: Alum salts as adjuvant2-Phenoxyethanol as antiseptic
Hib component
PRP: 10 mcg
conjugated to TT
Potentially deleterious interactions between vaccine components
Possible adverse consequences
• Reduced immunogenicity
• Increased reactogenicity
• Shortened shelf life
• Complicated manufacture
Antigens
Preservative(s)Adjuvant(s)
Contaminants
pH
Stabilizer(s) Excipient(s)
Infanrix penta and Infanrix hexa:Key objectives of clinical development
Demonstration of
safety and acceptable reactogenicity
immunogenicity in various schedules
persistence of antibodies up to the booster dose
protective efficacy of each vaccine component
lot-to-lot consistency
Infanrix penta and Infanrix hexa:Integrated clinical trial programme
Common inclusion and exclusion criteria
Common reactogenicity assessment
Common serological assays
Randomized controlled trials: predefined statistical criteria to demonstrate non-inferiority vs. licensed vaccines
Infanrix penta: primary immunization trialsStudy Country PI Schedule
(months)No. of infants receiving
Infanrix penta (ATP analysis)001 Turkey Kanra 3, 4, 5 20002 Finland Mertsola 2, 4, 6 30004 Canada Scheifele 2, 4, 6 50005 Belgium Blancke 3, 4, 5 563008 Belgium Lebacq 3, 4, 5 195011 Germany Zepp 3, 4, 5 4,696012 Lithuania Usonis 3, 4½, 6 549015 USA Ward 2, 4, 6 200016 Germany Zepp 3, 4, 5 182017 France Bégué 2, 3, 4 29019 Estonia Lutsar 3, 4½, 6 60023 Germany Schmitt 3, 4, 5 179025 France Cohen 2, 3, 4 159030 Moldavia Gylca 1½, 2½, 3½* 160044 USA Edwards 2, 4, 6 477
TOTAL : 7,549
* a dose of HBV was given at birth
Infanrix hexa: primary immunization trials
Study Country PI Schedule(months)
No. of infants receivingInfanrix hexa (ATP analysis)
001 USA Blatter 2, 4, 6 134
003 USA Blatter 2, 4, 6* 525 )
023 Germany Schmitt 3, 4, 5 179
025 France Cohen 2, 3, 4 166
027 USA Black 2, 4, 6 1076
031 Slovakia Avdicova 3, 5, 11 155
036 Australia Nolan 2, 4, 6 182
039 Germany Zepp 3, 4, 5 1581
040 Philippines Montellano 1½, 2½, 3½* 144
048 Germany Heininger 3, 4, 5 555
037 Germany Zepp 3, 4, 5 49
TOTAL : 4746
* one study group received a dose of HBV at birth
Infanrix penta + Hib vs. separate administration of antigens: study design
DTPa-HepB-IPV + Hib
DTPa-HepB-IPV + Hib DTPa-HepB + Hib + OPV
DTPa-HepB + IPV + Hib
DTPa + HepB + Hib + OPV
Group 2 mo 4 mo 6 mo
IPV
Combined
IPV-OPV
Separate(OPV)
All groups N = 100 enrolledStudy 015: Ward, USA
Immunogenicity of D, T and HBsAg
0
20
40
60
80
100
Anti-D Anti-T Anti-HBs
%
Ser
op
rote
ctio
n
GMTs: 1.3 0.8 3.7 2.3 1661 805
Combined (N=89-90) Separate (N=77-78)
anti-D, anti-T: IU/ml; anti-HBs: mIU/ml Study 015: Ward, USA
Immunogenicity of PT, FHA and PRN%
V
acci
ne
Res
po
nse
0
20
40
60
80
100
Anti-PT Anti-FHA Anti-PRN
GMTs: 97 47 119 153 150 109
Combined (N=91) Separate (N=77-78)
anti-PT, anti-FHA, anti-PRN: EL.U/ml Study 015: Ward, USA
Immunogenicity of Polio types 1, 2, and 3
0
20
40
60
80
100
Anti-Polio 1 Anti-Polio 2 Anti-Polio 3
%
Ser
op
rote
ctio
n
Combined (N=86) Separate OPV (N=73)
GMTs: 415 819 514 1262 1729 453
Study 015: Ward, USA
Immunogenicity of Polio types 1, 2, and 3
0
20
40
60
80
100
Anti-Polio 1 Anti-Polio 2 Anti-Polio 3
%
Ser
op
rote
ctio
n
Combined (N=86) Separate IPV (N=77)
GMTs: 415 213 514 329 1729 432
Study 015: Ward, USA
Study 015 - Local Reactions
Group 1 = Combined
DTPa-HepB-IPV
2 injections
Hib
Group 4 = Separate + OPV
DTPa
HepB
Hib
3 injections
OPV o o o
Dose 1 Dose 2 Dose 3
DTPa-HepB-IPV Any 17.0 17.7 20.0
(group 1) > 20 mm 2.0 1.0 0.0
DTPa Any 14.3 10.3 14.3
(group 4) > 20 mm 0.0 0.0 0.0
4-day follow-up period
Study 015: Incidence (%) of redness by dose
(N = 84 - 100 per dose)
Dose 1 Dose 2 Dose 3
DTPa-HepB-IPV Any 11.0 15.6 14.7
(group 1) > 20 mm 2.0 2.1 2.1
DTPa Any 7.1 10.3 10.7
(group 4) > 20 mm 1.0 1.1 0.0
4-day follow-up period
Study 015: Incidence (%) of swelling by dose
(N = 84 - 100 per dose)
Study 015: Incidence (%) of pain by dose
Dose 1 Dose 2 Dose 3
DTPa-HepB-IPV Any 35.0 26.0 22.1
(group 1) Grade 3 2.0 0.0 0.0
DTPa Any 33.7 19.5 21.4
(group 4) Grade 3 4.1 0.0 0.0
4-day follow-up period (N = 84 - 100 per dose)
Study 015: Incidence (%) of solicited general symptoms per subject
4-day follow-up period over the full vaccination course
DTPa-HepB-IPV + Hib DTPa+HepB+Hib+OPV
General Symptom % 95%CI % 95%CI
Diarrhea 26.0 (17.7 –35.7) 28.6 (19.9 – 38.6)
Fussiness 82.0 (73.1 – 89.0) 85.7 (77.2 – 92.0)
Loss of appetite 38.0 (28.5 – 48.3) 38.8 (29.1 – 49.2)
Sleeping less than usual 42.0 (32.2 – 52.3) 42.9 (32.9 – 53.3)
Sleeping more than usual 64.0 (53.8 – 73.4) 60.2 (49.8 – 70.0)
Unusual crying 6.0 (2.2 – 12.6) 6.1 (2.3 – 12.9)
Vomiting 13.0 (7.1 – 21.2) 16.3 (9.6 – 25.2)
Fever > 38°C/100.4°F 41.0 (31.3 – 51.3) 29.6 (20.8 – 39.7)
4-day follow-up period over the full vaccination course
DTPa-HepB-IPV + Hib DTPa+HepB+Hib+OPV
General Symptom % 95%CI % 95%CI
Diarrhea 2.0 (0.2 – 7.0) 1.0 (0.0 – 5.6)
Fussiness 7.0 (2.9 – 13.9) 11.2 (5.7 – 19.2)
Loss of appetite 1.0 (0.0 – 5.4) 2.0 (0.2 – 7.2)
Sleeping less than usual 1.0 (0.0 – 5.4) 4.1 (1.1 – 10.1)
Sleeping more than usual 1.0 (0.0 – 5.4) 2.0 (0.2 – 7.2)
Unusual crying 0.0 (0.0 – 3.6) 0.0 (0.0 – 3.7)
Vomiting 1.0 (1.0 – 0.0) 2.0 (0.2 – 7.2)
Fever > 39.5°C/103.2°F 3.0 (0.6 – 8.5) 2.0 (0.2 – 7.2)
Study 015: Incidence (%) of “grade 3” solicited general symptoms per subject
Infanrix hexa vs. separate administration of antigens (standard of care)
Group N Vaccine(s) # injections
Combined 134 DTPa-HBV-IPV/Hib 1
Separate 134 DTPa + HBV + Hib + OPV 3
Open, randomized, multicenter
Schedule: 2, 4, 6 months
Study 001: Blatter, USA
Immunogenicity of D, T and HBsAg
0
20
40
60
80
100
Anti-D Anti-T Anti-HBs
%
Ser
op
rote
ctio
n
Combined (N=134) Separate (N=134)
GMTs: 1.43 1.01 1.98 1.49 1240 934
anti-D, anti-T: IU/ml; anti-HBs: mIU/ml Study 001, Blatter, USA
Immunogenicity of PT, FHA, and PRN%
V
acci
ne
Res
po
nse
0
20
40
60
80
100
Anti-PT Anti-FHA Anti-PRN
Combined (N=134) Separate (N=134)
GMTs: 67.4 41.8 288 303 168 137
anti-PT, anti-FHA, anti-PRN: EL.U/ml Study 001: Blatter, USA
Immunogenicity of Polio types 1, 2, and 3
0
20
40
60
80
100
Anti-Polio 1 Anti-Polio 2 Anti-Polio 3
%
Ser
op
rote
ctio
n
Combined (N=134) Separate (N=134)
GMTs: 495 1278 507 1350 1275 368
Study 001: Blatter, USA
Immunogenicity of Hib: anti-PRP antibodies
100 % 96.9 %
%
Ser
op
rote
ctio
n
91.8 %84.0 %
Combined (N=134) Separate (N=134)
GMCs: 2.65 5.52
Study 001: Blatter, USA
0
20
40
60
80
100
> 0.15 mcg/ml > 1.0 mcg/ml
Study 001: reactogenicityStudy 001: reactogenicity
Pain
Grade 3
Redness
> 20 mm
Swelling
> 20 mm
Fever
> 39.5 °C
% s
ub
ject
s re
po
rtin
g t
he
sym
pto
m(r
egar
dle
ss o
f in
ject
ion
sit
e)
DTPa-HBV-IPV/Hib (N=134)
DTPa + HBV + Hib + OPV (N=134)
Reactogenicity of Infanrix hexa Reactogenicity of Infanrix hexa vsvs. whole-cell pertussis - . whole-cell pertussis - containing combinationcontaining combination
DTPa-HBV-IPV/Hib (N =166)
DTPw-IPV/Hib (Pentacoq TM) + HBV (Engerix TM) (N =82)
% s
ubje
cts
repo
rtin
g th
e sy
mpt
om(r
egar
dles
s of
inje
ctio
n si
te)
Pain
Grade 3
Redness
> 20 mm
Swelling
> 20 mm
Fever
> 39.5 °C
Study 025: Cohen, France, schedule 2-3-4
Infanrix hexa: seroprotection rates for antigens with established surrogate markers of protection(all studies, all schedules)
Antibody Definition of minimalseroprotective titre
% of subjects withseroprotective titres
anti-D 0.1 IU/ml* 98.5
anti-T 0.1 IU/ml* 99.2
anti-HBs 10 mIU/ml 98.5
anti-polio 1 1 : 8 99.2
anti-polio 2 1 : 8 94.5
anti-polio 3 1 : 8 98.8
* by ELISA
Infanrix hexa: D, T, Pa, HepB, IPV
Non-inferiority of Infanrix hexa post-primary vaccination as compared to licensed vaccines
– DTPa-IPV/Hib
– DTPw-IPV/Hib
– Separate administration of DTPa, HepB, Hib and OPV
Similar distribution of antibody titres (Reverse Cumulative Distribution Curves - RCCs)
DTPa-HBV-IPV/Hib
Anti-PT antibody titres following administration of Anti-PT antibody titres following administration of DTPa-HBV-IPV/Hib and of DTPa (Infanrix™) vaccineDTPa-HBV-IPV/Hib and of DTPa (Infanrix™) vaccine
RCCs generated for lots that induced the highest (*) and lowest (**) antibody response
Household contact study* Household contact study ** DTPa-HBV-IPV/Hib
Per
cen
tag
e o
f su
bjec
ts
Anti-PT antibody titre (EU/ml)
Study 048, PI: Heininger, Germany, schedule 3-4-5
Hib immunogenicity
Anti-PRP antibody titres are lower when Hib
vaccines are combined with DTPa-based
vaccines as compared to the separate injection
of the vaccines
Lancet 1999, 354: 2063-68
Infanrix hexa: Hib
In all clinical trials, regardless of vaccination schedule, 96 % of subjects achieved concentrations 0.15 µg/ml
Non-inferiority of Infanrix hexa as compared to licensed DTPa-IPV/Hib vaccine
Identical functional capacity of anti-PRP antibodies induced by Infanrix hexa and by licensed Hib vaccines
Effective induction of immune memory
Proven field effectiveness of DTPa/Hib andDTPa-IPV/Hib under conditions of routine use
• Subjects primed with 3 doses of Infanrix hexa(study 039)
• Randomised at 12-18 months to 3 booster groups
N
• DTPa-IPV/Hib 163• DTPa-IPV/Hib + HepB168• Infanrix hexa 544
Infanrix hexa as a 4th dose: reactogenicity
Study 058: Zepp, Germany
Incidence of solicited symptomsfollowing 3 different boosters
0
10
20
30
40
50
60
Redness Swelling Pain Fever > 38.0°C
DTPa-IPV/Hib (N=163)DTPa-IPV/Hib + HBV (N=168)Infanrix hexa (N=544)
% o
f su
bje
cts
wit
h a
sy
mp
tom
Incidence of solicited symptomsfollowing 3 different boosters
0
10
20
30
40
50
60
Redness Swelling Pain Fever
0
10
20
30
40
50
60
Redness Swelling Pain Fever
DTPa-IPV/Hib (N=163)DTPa-IPV/Hib + HBV (N=168)Infanrix hexa (N=544)
= Grade 3; fever > 39.5°C
% o
f su
bje
cts
wit
h a
sy
mp
tom
0
10
20
30
40
50
60
% o
f su
bje
cts
wit
h a
sym
pto
m
Irritability Sleepiness Loss of appetite
DTPa-IPV/Hib (N=163)DTPa-IPV/Hib + HBV (N=168) Infanrix hexa (N=544)
Incidence of solicited symptomsfollowing 3 different boosters
In all clinical trials,no cases reported of
Hypotonic hyporesponsiveness
Encephalopathy
AnaphylaxisInfanrix penta: 23 439 doses
Infanrix hexa: 15 920 doses
Infanrix penta and Infanrix hexa: conclusions
Protective efficacy not affected by combination of antigens
Tolerability of primary and booster doses in line with that
of other licensed vaccines
Reduced number of injections
Make room for new (pneumococcal, meningococcal) vaccines
Add value to current standard of medical care